N-Benzyloxymalimide for an easy access to 5-alkyl-3-pyrrolin-2-ones: Asymmetric synthesis of the mixed imide substructure of the potent immunosuppressant microcolin B

Article abstract of DOI:10.1016/j.tetasy.2010.04.063

O-Benzyl-N-benzyloxymalimide 12 has been synthesized as a useful variant of the chiral building blocks 9. The advantage of the malimide 12 over 9 was demonstrated by mild and high-yielding reductive N-deprotection of N-benzyloxylactams 18a-i to give a series of (4R,5S)-5-alkyl-4-hydroxy- pyrrolidin-2-ones, which are key intermediates for the asymmetric synthesis of pyrrolidines, pyrrolizidines, and indolizidines, as well as β-hydroxy γ-amino acids. Lactam ent-11a has been applied to the synthesis of the mixed imide 25, a key intermediate for the total synthesis of microcolin B, which also demonstrated that lactam ent-11a or 11a can serve as a latent form of the 5-methyl-3-pyrrolin-2-one substructure of majusculamide D 4, deoxymajusculamide D, and the jamaicamides A-C.

Full text of DOI:10.1016/j.tetasy.2010.04.063

Tetrahedron: Asymmetry 21 (2010) 895–902
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
N-Benzyloxymalimide for an easy access to 5-alkyl-3-pyrrolin-2-ones:
asymmetric synthesis of the mixed imide substructure of the potent
immunosuppressant microcolin B
Zhao-Bao Ye a, Jie Chen a, Wei-Hua Meng a, Pei-Qiang Huang a,b,
*
a Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen,
Fujian 361005, China
b The State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
O-Benzyl-N-benzyloxymalimide 12 has been synthesized as a useful variant of the chiral building blocks
9. The advantage of the malimide 12 over 9 was demonstrated by mild and high-yielding reductive
N-deprotection of N-benzyloxylactams 18a–i to give a series of (4R,5S)-5-alkyl-4-hydroxy-pyrrolidin-
2-ones, which are key intermediates for the asymmetric synthesis of pyrrolidines, pyrrolizidines, and
Received 28 January 2010
Accepted 6 April 2010
Available online 16 June 2010
indolizidines, as well as b-hydroxy c-amino acids. Lactam ent-11a has been applied to the synthesis of
the mixed imide 25, a key intermediate for the total synthesis of microcolin B, which also demonstrated
that lactam ent-11a or 11a can serve as a latent form of the 5-methyl-3-pyrrolin-2-one substructure of
majusculamide D 4, deoxymajusculamide D, and the jamaicamides A–C.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
HO
P2O
Ph
Protected trans- or cis-5-alkyl-4-hydroxy-pyrrolidin-2-ones A
(Fig. 1) are versatile intermediates for the synthesis of 3-pyrrolid-
inol-containing alkaloids such as preussin,1a pyrrolizidine,1b and
indolizidine alkaloids;1c naturally occurring anti- or syn-b-hydroxy
C9H19-n
R
O
N
N
Me
P1
preussin
A
c
-amino acid residues B/C,2 as well as 5-alkyl-3-pyrrolin-2-ones3 D
OH
OH
(Fig. 1). 5-Alkyl-3-pyrrolin-2-ones D are found in several bioactive
natural products,4 such as the immunosuppressive agents microc-
olins A, B, and D (1–3, Fig. 2),5 cytotoxins majusculamide 4 and
deoxymajusculamide D,6 jamaicamides A–C (e.g., 5–7),7 and feed-
ing deterrent ypaoamide 8.8
Microcolins A 1 and B 2 were isolated from a Venezuelan sample
of the blue–green alga Lyngbya majuscule,5 which exhibited very
potent immunosuppressive and antiproliferative properties.5,9,10 It
has been shown that microcolins A 1 and B 2 (EC50 = 0.02 and
4.1 nM, respectively) are more potent inhibitors of the human
two-way mixed lymphocyte response (MLR) than FK506 and cyclo-
sporin A (EC50 = 20 and 23 nM, respectively), two drugs currently in
clinical use in transplantation. In addition, the 3-pyrrolin-2-one
moietyhasbeenshowntobemandatoryfor theimmunosuppressive
activity.10 Microcolins B 2 and D 3 significantly inhibited adhesion
R
CO2H
R
CO2H
R
O
N
H
NH2
NH2
D
B
B
C
or ent-
a
a. statine (R = i-Bu)
b. AHPPA (R = Bn)
. (3R,4S)-AHPPA
(R = Bn)
c
b. (3S,4R,5S)-
isostatine
. ACHPA
(R = CH2-c-hex)
(R = s-Bu)
Figure 1. 5-Alkyl-4-hydroxy-pyrrolidin-2-ones
A
as versatile synthetic
intermediates.
testing9,10 and development of novel biological probes.14 On the
other hand, the jamaicamides exhibited sodium channel blocking
cell (IC50 = 0.15 and 0.9 lM, respectively), without producing a
properties at 5
theH-460humanlungandneuro-2amouseneuroblastomacelllines
with LC50 about 15 M.
lM as wellas moderatecytotoxicityactivities against
cytotoxic effect on either HL-60 or CHO-ICAM-1 cells.11 The total
syntheses of microcolins A 112 and B13 2 as well as several synthetic
analogues of microcolin A have been reported for both biological
l
The synthesis of 5-alkyl-3-pyrrolin-2-one substructures is a key
in the total synthesis of these natural products.12,13 Although
several methods have been reported for the synthesis of alkyl-3-
* Corresponding author. Fax: +86 592 2186400.
E-mail address: pqhuang@xmu.edu.cn (P.-Q. Huang).
pyrrolin-2-ones,12,13,15,16 most of them used
a-amino acids as the
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.063

896
Z.-B. Ye et al. / Tetrahedron: Asymmetry 21 (2010) 895–902
be cleaved with either ceric ammonium nitrate (CAN, oxidative
R1
deprotection),19 or RhCl3 ꢀ H2O (isomerization-hydrolysis).20 In
view of the importance of the protecting group strategy in the total
synthesis of natural products,21 we investigated the use of OBn as
an imides/amides N-protecting group,22 which has been shown to
be cleavable under mild conditions with SmI2.23,24 Herein, we re-
port the synthesis and regio-/diastereoselective reductive alkyl-
ation of malimide 12, as well as the synthesis of the mixed imide
25, a key intermediate for the total synthesis of microcolin B.
O
O
H
N
N
Me
N
N
O
O
N
O
OR2
microcolin A (R1 = OH, R2 = Ac, 1)
O
1
2
2
microcolin B (R =H, R = Ac,
)
microcolin D (R1=OH, R2=H, 3)
OMe
2. Results and discussion
OH
The work started with the synthesis of (S)-malimide 12 from
(S)-malic acid and commercially available O-benzylhydroxylamine
hydrochloride salt. Thus, the O-benzylmalic acid 14 was prepared
from the known diethyl O-benzylmalate 13 by saponification
(Scheme 1). The condensation of O-benzylmalic acid 13 with O-
benzylhydroxylamine hydrochloride salt by a one-pot three-step
procedure25 led smoothly to the formation of malimide 12 in 88%
overall yield.
O
O
H
N
N
Me
N
N
O
O
N
OAc
O
majusculamide D 4
O
Cl
After outlining the route to the malimide 12, we proceeded to
investigate its reductive alkylation. Treatment of O,O0-bisbenzyl-
1-hydroxymalimide 12 with methyl magnesium iodide in CH2Cl2
at ꢁ78 °C for 30 min resulted in the formation of the desired C-2
adduct 15a in 79% yield, along with small amounts of C-5 adduct
16a and dimethylated side product 17a. The C-2/C-5 regioselectiv-
ity was 95:5. The C-2 addition product 15a is a mixture of two dia-
stereomers in a 1.3:1 ratio as indicated by 1H NMR analysis. It was
observed that the ratio improved to 9.3:1 upon standing the mix-
ture at 0–5 °C for seven days. Recrystallization then gave the pure
major diastereomer, whose stereochemistry was determined as
trans by NOESY experiments (Fig. 4).
R
jamaicamide A (R = C CBr, 5)
jamaicamide B (R = C CH, 6)
O
N
H
MeO
jamaicamide C (R = CH=CH2, 7)
OH
Me
O
O
N
O
MeO
N
N
H
O
O
ypaoamide 8
BnO
O
BnO
1) AcCl
Figure 2. Some 5-alkyl-3-pyrrolin-2-one substructure-containing natural products.
2) BnONH2·HCl
Py, CH2Cl2
RO2C
CO2R
O
N
OBn
12
starting materials,12,13,15 which might suffer from partial racemiza-
tion,13b,15b,d and a lack of generality. A non-amino acid-based
approach would offer a greater flexibility for the synthesis of ana-
logues bearing different C-5 substituents, which is crucial for SAR
studies. In addition, methods allowing the cleavage of N-protecting
group under racemization-free conditions to give the required
5-alkyl-3-pyrrolin-2-one substructures are even rare.16a,b
In recent years, we have been engaged in the development of the
protected (S) or (R)-malimides 9 as versatile chiral building blocks
for the asymmetric synthesis of N-containing bioactive natural
products.17 In this methodology, after the key trans- or cis-diaste-
reoselective reductive alkylation reactions (Fig. 3, 9–10), the
smooth and efficient conversion of the 5-alkyl-4-hydroxy-pyrroli-
din-2-ones 10–11 by N-deprotection turned out to be another key
step in the synthesis of natural products such as melleumin A,18a
pyrrolam A,18b and ypaoamide18c 8. In this regard, p-methoxyben-
zyl group (PMB)17a,18b and allyl group17,18a,c were introduced as
the N-protecting groups, which, at the stage of lactams 10, could
LiOH
EtOH-H2O
95%
13. R = Et
3) AcCl
88%
14
. R = H
BnO
O
BnO
HO
Me
MeMgI, CH2Cl2
OH
Me
+
30 min., −78 °C
O
N
OBn
N
OBn
79%
16a
15a
+
Et3SiH, BF3·OEt2
BnO
OBn O
CH2Cl2, −78 °C
Me
NH
OBn
Me
O
N
OBn
18a
Me
OH
17a
Scheme 1.
BnO
O
BnO
R
BnO
R
BnO
O
Ph
H
H
3.92
4.59
2.74
H
H
O
O
O
O
N
N
N
O
H 2.33
N
OBn
12
H
11
3.73
1.53
P
10
HO
P
9
O
N
Me
OBn
weak
(a. P = PMB; b. P = Bn; c. P =Allyl)
Figure 3.
Figure 4. Observed NOESY correlations (in part) of compound trans-15a.

Z.-B. Ye et al. / Tetrahedron: Asymmetry 21 (2010) 895–902
897
After securing the highly regioselective Grignard reagent addi-
BnO
BnO
tion to malimide 12, the reductive alkylation of 12 was studied.
Thus, the reaction mixture, obtained from the methyl Grignard re-
agent addition, was subjected to boron trifluoride etherate-medi-
ated triethylsilane reduction26 to give predominantly 18a, along
with small amounts of isomeric lactam 19a and lactone 20a
(Scheme 2). The stereochemistry of compounds 18 was assigned
as trans according to the observed vicinal coupling constants27
(J4,5 = 3.3 Hz for 18a). This was further confirmed by the conversion
of compound 18a to the known compound 25.13 Extension of this
procedure to other Grignard reagents led to corresponding prod-
ucts 18b–i in similar regioselectivity (Table 1, entries 3–10).
SmI2, CH3OH
R
O
R
O
N
OBn
18a-i
THF, rt, 3 h
100%
N
H
11a-i
Scheme 3.
carbonylation (Boc2O, NEt3, CH2Cl2, 0 °C), and EDC-mediated cou-
pling (C6F5OH, EDC, CH2Cl2, rt, 8 h) (Scheme 4). Treatment of the
lactam ent-11a, prepared from (R)-malic acid according to Schemes
1–3, with n-butyllithium in THF at ꢁ78 °C gave the imidate inter-
mediate that was subjected to reaction with the activated ester 22
to yield the mixed imide 23 in 81% yield. The debenzylation of 23
was achieved by catalytic transfer hydrogenation (HCO2H, 10% Pd/
C, EtOH), which gave alcohol 24 in 81% yield. For the transforma-
tion of compound 24 to the final product 25, two methods were
adopted. The first approach consisted of the treatment of a CH2Cl2
solution of 24 with (Boc)2O (1.0 mol equiv)/DMAP (0.1 mol equiv)
at 0 °C, which afforded directly the desired product 25 in 71% yield
BnO
1) RMgX, CH2Cl2, −78 °C
2) Et3SiH, BF3·OEt2, CH2Cl2
O
O
N
OBn
12
−
78 °C to rt
BnO
R
BnO
O
BnO
R
{½a 2D0
ꢂ
¼ ꢁ80 (c 1.0, CHCl3)}; lit. ½a D20
ꢂ
¼ ꢁ85 (c 1.1, CHCl3);13a
½
a 2D0
ꢂ
¼ ꢁ92 (c 1, CHCl3) for a 5:1 diastereomeric mixture13b}. When
+
+
R
O
O
N
OBn
N
OBn
18
O
the reaction was run at 30 °C, partial racemization occurred as
R
indicated by the optical rotation of the product {½a D20
¼ ꢁ64 (c
ꢂ
1.0, CHCl3)}. The second method afforded a better yield. In the
event, compound 24 was allowed to react with MsCl/Et3N at
ꢁ20 °C for 1 h. During the work-up procedure, elimination of the
mesylate intermediate occurred spontaneously to give the desired
20
19
Scheme 2.
compound 25 in 83% yield {½a D20
¼ ꢁ80 (c 1.0, CHCl3)}.
ꢂ
Table 1
Reductive alkylation of malimide 12 and subsequent cleavages of the N–O bonds
Entry RMgX
Regioselectivity N-Benzyloxylactams Lactams 11
C6F5OH, EDC
OC6F5
(C2/C5)a
18 (% yield
(% yield from
COOH
N
N
Boc
from 12)b
18)b
CH2Cl2, rt, 8 h
84%
O
Boc
22
1
2
MeMgI
MeMgI
95:5
95:5
93:7
92:8
91:9
91:9
90:10
18a (65)
ent-18ac (65)
18b (64)
18c (65)
11a (100)
ent-11ac (100)
11b (91)
21
3
EtMgBr
BnO
4
5
6
7
n-PrMgBr
i-PrMgBr
n-BuMgBr
i-BuMgBr
11c (96)
11d (94)
11e (93)
11f (100)
11g (91)
18d (73)
18e (60)
18f (74)
18g (59)
18h (62)
18i (64)
OBn
O
ent-
N
11a
10% Pd-C
H
8
9
n-C7H15MgBr 92:8
n-C8H17MgBr 91:9
11h (100)
11i (95)
N
HCOOH, EtOH
81%
n-BuLi, THF
−78 °C
N
Boc
10
PhMgBr
88:12
O
O
a
b
c
Ratio determined by chromatographic separation.
Isolated yield.
Synthesized from (R)-malic acid.
81%
23
OH
As a demonstration of the suitability of compounds 18a–i as
(Boc)2O, DMAP
N
N
ready precursors of the lactams 11a–i, cleavages of the N–O bonds
in compound 18a–i were undertaken. Although a number of meth-
ods have been reported for the cleavage of the N–O bond, including
the two-step procedure (O-debenzylation-SmI2-mediated cleav-
age) reported by Keck,23a we elected to undertake a direct SmI2-
mediated cleavage of this N–O bond. To our satisfaction, in the
presence of 10 mol equiv of methanol, the reaction of N-benzyl-
oxylactam 18a with 4 mol equiv of SmI2 in THF (0.1 M, rt, 3 h)
cleanly produced the desired lactam 11a in quantitative yield
(Scheme 3 and Table 1, column 4, entry 1). The SmI2-mediated
cleavage of N–O bond compound 18b–i gave the corresponding
5-alkylpyrrolidin-2-one derivatives 11a–i in 91–100% yields
(Table 1, column 4, entries 3–10).
N
Boc
N
Boc
CH2Cl2
71%
O
O
O
O
25
24
Scheme 4.
3. Conclusion
In summary, by using O-benzyl-N-benzyloxymalimide 12 as a
useful variant of the building blocks 9, the longstanding problem
associated with the difficulties in the N-deprotection of the
lactams obtained from the building blocks 9 has been resolved. N-
benzyloxymalimide 12 not only keeps the high regio- and diastere-
oselectivities in the reductive alkylation reactions, but also affords
the advantage of allowing a high-yielding N-deprotection of the
resultant N-benzyloxylactams under very mild conditions. Using
this method, the asymmetric synthesis of the mixed imide substruc-
To demonstrate the feasibility of lactams 11a–i to serve as a la-
tent form of the corresponding 5-alkyl-3-pyrrolin-2-ones D, we
undertook the synthesis of the mixed imide portion 25 of microc-
olin B 2. For this purpose,
L-proline was converted successively to
Boc-(S)-proline 21 and pentafluorophenyl ester28 22 by butoxy-

898
Z.-B. Ye et al. / Tetrahedron: Asymmetry 21 (2010) 895–902
ture 25 of the potent immunosuppressant microcolin B has been
disclosed. This method thus detached a flexible non-amino acid-
based approach to different 5-alkyl-3-pyrrolin-2-ones D, which
are found as key substructures in several bioactive natural products.
10.83 (br s, 2H, COOH); 13C NMR (100 MHz, DMSO-d6) d: 47.8,
82.9, 85.2, 138.0, 138.2, 138.6, 148.5, 181.7, 182.7; MS (ESI): m/z
247 (M+Na+, 100).
4.3.2. (R)-2-(Benzyloxy)succinic acid ent-14
White semi-solid; ½a D20
¼ þ49:6 (c 1.2, CH3OH).
ꢂ
4. Experimental section
4.1. General
4.4. Preparation of compounds 12 and ent-12
4.4.1. (S)-1,3-Dibenzyloxypyrrolidin-2,5-dione 12
Melting points were determined on a WRS-1B melting point
apparatus. Infrared spectra were measured with a Nicolet Avatar
360 FT-IR spectrometer using film KBr pellet techniques. 1H NMR
spectra were recorded in CDCl3 on a Bruker Av 400 spectrometer
with tetramethylsilane as an internal standard. Chemical shifts
are expressed in d (ppm) units downfield from TMS. Mass spectra
were recorded on a Bruker Dalton ESquire 3000 plus liquid chro-
matography–mass spectrum (direct injection). HRMS spectra were
recorded on a Shimadzu LC–MS-IT-TOF apparatus. Optical rota-
tions were measured with a Perkin–Elmer 341 automatic polarim-
eter. Silica gel (300–400 mesh) was used for flash column
chromatography, eluting (unless otherwise stated) with ethyl ace-
tate/petroleum ether (PE) (60–90 °C) mixture. THF was distilled
over sodium benzophenone ketyl under N2. Dichloromethane
was distilled over calcium hydride under N2.
A mixture of the known (S)-2-(benzyloxy)succinic acid 14
(1.78 g, 7.95 mmol) and AcCl (2.8 mL, 39.75 mmol) was refluxed
for 2 h and then concentrated under reduced pressure. To the
resulting mixture were added successively BnONH2ꢃHCl (1.39 g,
8.74 mmol) and CH2Cl2 (26.5 mL). The mixture was cooled to 0–
5 °C and then pyridine (1.3 mL, 16.69 mmol) was added dropwise.
The resultant mixture was stirred at room temperature overnight.
The mixture was concentrated under reduced pressure and the res-
idue wasdissolvedinAcCl(2.8 mL,39.75 mmol)andrefluxedfor2 h.
After concentration under reduced pressure, the residue was puri-
fied by flash column chromatography on silica gel (EtOAc/PE = 1:5)
to give compound 12 (2.17 g, yield: 88%) as white crystals. Mp
115 °C (Et2O/EtOAc = 7:1); ½a D20
ꢂ
¼ ꢁ90:2 (c 1.0, CHCl3); IR (film)
m
max: 1727, 1497, 1456, 1388, 1222, 1208, 1068, 1018 cmꢁ1 1H
;
NMR (400 MHz, CDCl3) d: 2.60 (dd, J = 3.7, 18.0 Hz, 1H, H-4), 2.91
(dd, J = 8.3, 18.0 Hz, 1H, H-4), 4.27 (dd, J = 3.7, 8.3 Hz, 1H, H-3),
4.74 (d, J = 11.7 Hz, 1H, CHOCH2Ph), 4.95 (d, J = 11.7 Hz, 1H,
CHOCH2Ph), 5.12 (s, 2H, NOCH2Ph), 7.31–7.49 (m, 10H, Ph-H) ppm;
13C NMR (100 MHz, CDCl3) d: 34.2, 69.3, 72.9, 78.8, 128.2, 128.3,
128.5, 128.6, 129.5, 129.9, 133.1, 136.4, 168.6, 170.2; MS (ESI): m/z
350 (M+K+, 100). Anal. Calcd for C18H17NO4: C, 69.44; H, 5.50; N,
4.50. Found: C, 69.80; H, 5.63; N, 4.71.
4.2. Preparation of compounds 13 and ent-13
4.2.1. Diethyl (S)-2-(benzyloxy)succinate 13
To a mixture of diethyl (S)-malate (2.15 g, 11.32 mmol), Ag2O
(5.25 g, 22.64 mmol), and EtOAc (37.7 mL) was added BnBr
(2.0 mL, 16.98 mmol). After stirring in the dark for five days at
room temperature, the mixture was filtered through Celite and
concentrated under reduced pressure. The residue was purified
by flash column chromatography on silica gel (EtOAc/PE = 1:20)
to give compound 13 (3.01 g, yield: 95%) as a colorless oil.
4.4.2. (R)-1,3-Dibenzyloxypyrrolidin-2,5-dione ent-12
Mp 114 °C; ½a 2D0
¼ þ90:0 (c 1.2, CHCl3).
ꢂ
½
a 2D0
ꢂ
¼ ꢁ59:9 (c 1.2, CHCl3);29 IR (film)
mmax: 2983, 1737, 1274,
4.5. Typical procedure for the reductive alkylation of N-
benzyloxymalimide 12
1162, 1120, 1026 cmꢁ1 1H NMR (400 MHz, CDCl3) d: 1.23 (t,
;
J = 7.1 Hz, 3H, CH2CH3), 1.28 (t, J = 7.1 Hz, 3H, CH2CH3), 2.76 (dd,
J = 7.8, 16.0 Hz, 1H, CH2C@O), 2.81 (dd, J = 5.2, 16.0 Hz, 1H,
CH2C@O), 4.136 (q, J = 7.1 Hz, 1H, OCH2CH3), 4.144 (q, J = 7.1 Hz,
1H, OCH2CH3), 4.21 (q, J = 7.1 Hz, 1H, OCH2CH3), 4.22 (q,
J = 7.1 Hz, 1H, OCH2CH3). 4.39 (dd, J = 5.2, 7.8 Hz, 1H, CHOBn),
4.54 (d, J = 11.4 Hz, 1H, OCH2Ph), 4.77 (d, J = 11.4 Hz, 1H, OCH2Ph),
7.27–7.36 (m, 5H, Ph-H); 13C NMR (100 MHz, CDCl3) d: 14.0 (2C),
37.9, 60.7, 61.1, 72.9, 74.6, 127.8, 127.9, 128.2, 137.2, 169.9,
171.2; MS (ESI): m/z 303 (M+Na+, 100).
To
a
cooled (ꢁ78 °C) solution of malimide 12 (100 mg,
0.32 mmol) in anhydrous CH2Cl2 (6.4 mL) was added dropwise a
solution of CH3MgI (2 M, 0.35 mL, 0.70 mmol) in Et2O under a
nitrogen atmosphere. After stirring at ꢁ78 °C for 30 min, the reac-
tion was quenched with saturated NH4Cl (0.5 mL) and the mixture
was extracted with EtOAc (3 ꢀ 10 mL). The combined extracts
were washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. Filtration through a
short pad of column gave a mixture of compounds 15a, 16a, and
17a, which was used as it was in the next step.
4.2.2. Diethyl (R)-2-(benzyloxy)succinate ent-13
½
a 2D0
ꢂ
¼ þ59:9 (c 1.0, CHCl3).
The mixture of 15a, 16a, and 17a was dissolved in anhydrous
CH2Cl2 (3.2 mL) under a nitrogen atmosphere. The solution was
cooled to ꢁ78 °C, then Et3SiH (0.51 mL, 3.21 mmol) and BF3ꢃOEt2
(0.12 mL, 0.96 mmol) were added. After stirring at ꢁ78 °C for 3 h,
the reaction temperature was allowed to rise slowly to room tem-
perature overnight and then the reaction was quenched by a satu-
rated NaHCO3 (0.6 mL). After extraction with CH2Cl2 (3 ꢀ 10 mL),
the combined extracts were washed with brine, dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica
gel (EtOAc/PE = 1:3) to give compound 18a (65 mg, yield over two
steps: 65%).
4.3. Preparation of compounds 14 and ent-14
4.3.1. (S)-2-(Benzyloxy)succinic acid 14
A mixture of malate derivative 13 (3.01 g, 10.75 mmol) and
LiOHꢃH2O (1.81 g, 43.00 mmol) in 20.3 mL of EtOH–H2O (3:1) was
stirred overnight at 0–5 °C. The solvent was removed under re-
duced pressure. The residue was acidified by a concentrated HCl
to reach pH 2. After concentration under reduced pressure, the res-
idue was purified by flash column chromatography on silica gel to
yield compound 14 (2.36 g, yield: 98%) as white crystals (lit.30 mp
60–61 °C). ½a 2D0
ꢂ
¼ ꢁ56:9 (c 1.9, CH3OH); IR (film)
mmax: 3411, 1598,
1415, 1092 cmꢁ1; 1H NMR (400 MHz, DMSO-d6) d: 3.22 (dd, J = 8.3,
16.2 Hz, 1H, CH2COOH), 3.35 (dd, J = 4.5, 16.2 Hz, 1H, CH2COOH),
4.90 (dd, J = 4.5, 8.3 Hz, 1H, CHOBn), 5.02 (d, J = 11.4 Hz, 1H,
CH2Ph), 5.25 (d, J = 11.4 Hz, 1H, CH2Ph), 7.70–7.84 (m, 5H, Ph-H),
4.5.1. (4S,5R)-1,4-Dibenzyloxy-5-methylpyrrolidin-2-one 18a
Compound 18a: colorless oil. Yield over two steps: 65%.
½
a 2D0
ꢂ
¼ þ89:7 (c 1.0, CHCl3); IR (film)
m
max: 3034, 2963, 2930,
;
2872, 1715, 1453, 1379, 1101, 1064 cmꢁ1
1H NMR (400 MHz,

Z.-B. Ye et al. / Tetrahedron: Asymmetry 21 (2010) 895–902
899
CDCl3) d: 1.17 (d, J = 6.5 Hz, 3H, CH3), 2.38 (dd, J = 3.7, 17.3 Hz, 1H,
H-3), 2.64 (dd, J = 7.3, 17.3 Hz, 1H, H-3), 3.53 (dq, J = 3.3, 6.5 Hz, 1H,
H-5), 3.69 (ddd, J = 3.3, 3.7, 7.3 Hz, 1H, H-4), 4.40 (d, J = 11.8 Hz, 1H,
CHOCH2Ph), 4.45 (d, J = 11.8 Hz, 1H, CHOCH2Ph), 4.96 (d,
J = 10.7 Hz, 1H, NOCH2Ph), 5.00 (d, J = 10.7 Hz, 1H, NOCH2Ph),
7.28–7.44 (m, 10H, Ph-H); 13C NMR (100 MHz, CDCl3) d: 16.4,
34.4, 59.5, 70.7, 75.3, 76.5, 127.3, 127.7, 128.2 (2C), 128.5, 129.3,
134.8, 137.0, 167.8; MS (ESI): m/z 334 (M+Na+, 100). Anal. Calcd
for C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C, 72.90; H,
6.65; N, 4.90.
1713, 1450, 1089, 1069 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d: 0.87
(t, J = 7.0 Hz, 3H, CH3), 1.14–1.38 (m, 5H, C3H6CH3), 1.66–1.74 (m,
1H, CH2CHN), 2.39 (dd, J = 2.5, 17.4 Hz, 1H, H-3), 2.61 (dd, J = 7.2,
17.4 Hz, 1H, H-3), 3.41 (ddd, J = 2.3, 3.8, 8.2 Hz, 1H, H-5), 3.76
(ddd, J = 2.3, 2.5, 7.2 Hz, 1H, H-4), 4.38 (d, J = 11.8 Hz, 1H,
CHOCH2Ph), 4.42 (d, J = 11.8 Hz, 1H, CHOCH2Ph), 4.98 (d,
J = 11.1 Hz, 1H, NOCH2Ph), 5.00 (d, J = 11.1 Hz, 1H, NOCH2Ph),
7.28–7.45 (m, 10H, Ph-H) ppm; 13C NMR (100 MHz, CDCl3) d:
13.8, 22.5, 26.9, 30.2, 34.9, 63.9, 70.6, 73.7, 77.1, 127.6, 127.9,
128.5 (2C), 128.8, 129.6, 135.2, 137.4, 167.8 ppm. MS (ESI): m/z
376 (M+Na+, 100). Anal. Calcd for C22H27NO3: C, 74.76; H, 7.70;
N, 3.96. Found: C, 74.50; H, 7.85; N, 4.10.
4.5.2. (4R,5S)-1,4-Dibenzyloxy-5-methylpyrrolidin-2-one ent-
18a
½
a 2D0
ꢂ
¼ ꢁ95:5 (c 1.2, CHCl3).
4.5.7. (4S,5R)-1,4-Dibenzyloxy-5-isobutylpyrrolidin-2-one 18f
Compound 18f: colorless oil. Yield over two steps: 74%.
4.5.3. (4S,5R)-1,4-Dibenzyloxy-5-ethylpyrrolidin-2-one 18b
Compound 18b: colorless oil. Yield over two steps: 64%.
½
a 2D0
ꢂ
¼ þ90:7 (c 1.1, CHCl3); IR (film)
m
max: 2959, 1711, 1590,
;
1449, 1383, 1366, 1093, 1068, 1042 cmꢁ1
1H NMR (400 MHz,
½
a 2D0
ꢂ
¼ þ86:8 (c 1.2, CHCl3); IR (film)
m
max: 3029, 2963, 2930,
CDCl3) d: 0.82 (d, J = 6.2 Hz, 3H, CH3), 0.87 (d, J = 6.2 Hz, 3H, CH3),
1.09–1.17 (m, 1H, CHCH3), 1.55–1.65 (m, 2H, CH2CHN), 2.39 (dd,
J = 2.1, 17.4 Hz, 1H, H-3), 2.61 (dd, J = 6.9, 17.4 Hz, 1H, H-3), 3.43
(ddd, J = 1.9, 4.0, 9.2 Hz, 1H, H-5), 3.72 (ddd, J = 1.9, 2.1, 6.9 Hz,
1H, H-4), 4.36 (d, J = 11.8 Hz, 1H, CHOCH2Ph), 4.40 (d, J = 11.8 Hz,
1H, CHOCH2Ph), 4.97 (d, J = 10.9 Hz, 1H, NOCH2Ph), 5.00 (d,
J = 10.9 Hz, 1H, NOCH2Ph), 7.27–7.45 (m, 10H, Ph-H); 13C NMR
(100 MHz, CDCl3) d: 22.0, 23.2, 24.5, 34.5, 39.7, 62.3, 70.6, 74.3,
77.2, 127.5, 127.9, 128.4, 128.5, 128.8, 129.7, 135.2, 137.3, 167.7;
MS (ESI): m/z 376 (M+Na+, 100). Anal. Calcd for C22H27NO3: C,
74.76; H, 7.70; N, 3.96. Found: C, 74.37; H, 8.05; N, 3.86.
1714, 1458, 1072 cmꢁ1 1H NMR (400 MHz, CDCl3) d: 0.85 (t,
;
J = 7.5 Hz, 3H, CH3), 1.43 (qdd, J = 7.5, 8.0, 15.1 Hz, 1H, CH2CH3),
1.74 (dqd, J = 3.8, 7.5, 15.1 Hz, 1H, CH2CH3), 2.40 (dd, J = 2.5,
17.4 Hz, 1H, H-3), 2.61 (dd, J = 7.2, 17.4 Hz, 1H, H-3), 3.39 (ddd,
J = 2.3, 3.8, 8.0 Hz, 1H, H-5), 3.77 (ddd, J = 2.3, 2.5, 7.2 Hz, 1H, H-
4), 4.38 (d, J = 11.8 Hz, 1H, CHOCH2Ph), 4.42 (d, J = 11.8 Hz, 1H,
CHOCH2Ph), 4.98 (d, J = 11.0 Hz, 1H, NOCH2Ph), 5.00 (d,
J = 11.0 Hz, 1H, NOCH2Ph), 7.28–7.45 (m, 10H, Ph-H); 13C NMR
(100 MHz, CDCl3) d: 9.0, 23.3, 34.9, 64.8, 70.6, 73.1, 77.0, 127.5,
127.9, 128.4 (2C), 128.7, 129.5, 135.0, 137.2, 167.8; MS (ESI): m/z
348 (M+Na+, 100). Anal. Calcd for C20H23NO3: C, 73.82; H, 7.12;
N, 4.30. Found: C, 73.62; H, 6.83; N, 3.92.
4.5.8. (4S,5R)-1,4-Dibenzyloxy-5-heptylpyrrolidin-2-one 18g
Compound 18g: colorless oil. Yield over two steps: 59%.
4.5.4. (4S,5R)-1,4-Dibenzyloxy-5-propylpyrrolidin-2-one 18c
Compound 18c: colorless oil. Yield over two steps: 65%.
½
a 2D0
ꢂ
¼ þ62:7 (c 0.6, CHCl3); IR (film)
mmax: 2926, 2855, 1715,
1453, 1101, 1068 cmꢁ1 1H NMR (400 MHz, CDCl3) d: 0.88 (t,
;
½
a 2D0
ꢂ
¼ þ88:7 (c 1.0, CHCl3); IR (film)
m
max: 2956, 2933, 1713,
J = 6.9 Hz, 3H, CH3), 1.16–1.36 (m, 11H, C6H12CH3), 1.66–1.72 (m,
1H, CH2CHN), 2.39 (dd, J = 2.5, 17.4 Hz, 1H, H-3), 2.61 (dd, J = 7.2,
17.4 Hz, 1H, H-3), 3.40 (ddd, J = 2.2, 3.8, 8.2 Hz, 1H, H-5), 3.75
(ddd, J = 2.2, 2.5, 7.2 Hz, 1H, H-4), 4.37 (d, J = 11.8 Hz, 1H,
CHOCH2Ph), 4.41 (d, J = 11.8 Hz, 1H, CHOCH2Ph), 4.97 (d,
J = 11.2 Hz, 1H, NOCH2Ph), 5.00 (d, J = 11.2 Hz, 1H, NOCH2Ph),
7.27–7.45 (m, 10H, Ph-H); 13C NMR (100 MHz, CDCl3) d: 14.0,
22.6, 24.8, 29.1, 29.4, 30.5, 31.7, 34.8, 63.8, 70.6, 73.6, 77.1,
127.6, 127.9, 128.5 (2C), 128.8, 129.6, 135.2, 137.3, 167.8; MS
(ESI): m/z 418 (M+Na+, 100). Anal. Calcd for C25H33NO3: C, 75.91;
H, 8.41; N, 3.54. Found: C, 75.60; H, 8.65; N, 3.70.
1453, 1069 cmꢁ1 1H NMR (400 MHz, CDCl3) d: 0.88 (t, J = 7.2 Hz,
;
3H, CH3), 1.18–1.37 (m, 3H, C2H4CH3), 1.63–1.71 (m, 1H, CH2CHN),
2.38 (dd, J = 2.4, 17.4 Hz, 1H, H-3), 2.60 (dd, J = 7.2, 17.4 Hz, 1H, H-
3), 3.42 (ddd, J = 2.2, 4.0, 7.8 Hz, 1H, H-5), 3.75 (ddd, J = 2.2, 2.4,
7.2 Hz, 1H, H-4), 4.37 (d, J = 11.8 Hz, 1H, CHOCH2Ph), 4.41 (d,
J = 11.8 Hz, 1H, CHOCH2Ph), 4.97 (d, J = 11.0 Hz, 1H, NOCH2Ph),
4.99 (d, J = 11.0 Hz, 1H, NOCH2Ph), 7.25–7.45 (m, 10H, Ph-H)
ppm; 13C NMR (100 MHz, CDCl3) d: 13.9, 18.1, 32.7, 34.8, 63.6,
70.6, 73.7, 77.0, 127.5, 127.8, 128.4 (2C), 128.7, 129.5, 135.1,
137.3, 167.7 ppm. MS (ESI): m/z 340 (M+H+, 100). Anal. Calcd for
C21H25NO3: C, 74.31; H, 7.42; N, 4.13. Found: C, 74.33; H, 7.39;
N, 4.15.
4.5.9. (4S,5R)-1,4-Dibenzyloxy-5-octylpyrrolidin-2-one 18h
Compound 18h: colorless oil. Yield over two steps: 62%.
4.5.5. (4S,5R)-1,4-Dibenzyloxy-5-isopropylpyrrolidin-2-one 18d
Compound 18d: colorless oil. Yield over two steps: 73%.
½
a 2D0
ꢂ
¼ þ64:3 (c 1.1, CHCl3); IR (film)
mmax: 2924, 2853, 1713,
1454, 1089, 1069 cmꢁ1 1H NMR (400 MHz, CDCl3) d: 0.89 (t,
;
½
a 2D0
ꢂ
¼ þ69:5 (c 1.3, CHCl3); IR (film)
m
max: 2969, 2928, 1707,
J = 6.9 Hz, 3H, CH3), 1.16–1.36 (m, 13H, C7H14CH3), 1.66–1.72 (m,
1H, CH2CHN), 2.38 (dd, J = 2.6, 17.4 Hz, 1H, H-3), 2.61 (dd, J = 7.2,
17.4 Hz, 1H, H-3), 3.41 (ddd, J = 2.3, 3.9, 8.2 Hz, 1H, H-5), 3.75
(ddd, J = 2.3, 2.6, 7.2 Hz, 1H, H-4), 4.37 (d, J = 11.8 Hz, 1H,
CHOCH2Ph), 4.42 (d, J = 11.8 Hz, 1H, CHOCH2Ph), 4.97 (d,
J = 11.1 Hz, 1H, NOCH2Ph), 5.00 (d, J = 11.1 Hz, 1H, NOCH2Ph),
7.25–7.45 (m, 10H, Ph-H) ppm; 13C NMR (100 MHz, CDCl3) d:
14.0, 22.6, 24.7, 29.1, 29.3, 29.4, 30.5, 31.7, 34.8, 63.8, 70.6, 73.6,
77.0, 127.5, 127.9, 128.4 (2C), 128.7, 129.5, 135.2, 137.3,
167.8 ppm; MS (ESI): m/z: 410 (M+H+, 100). Anal. Calcd for
C26H35NO3: C, 76.25; H, 8.61; N, 3.42. Found: C, 76.30; H, 8.62;
N, 3.40.
1449, 1065 cmꢁ1 1H NMR (400 MHz, CDCl3) d: 0.78 (d, J = 6.9 Hz,
;
3H, CHCH3), 0.91 (d, J = 6.9 Hz, 3H, CHCH3), 2.10 (dq, J = 3.8,
6.9 Hz, 1H, CHCH3), 2.40 (dd, J = 2.0, 17.6 Hz, 1H, H-3), 2.55 (dd,
J = 7.3, 17.6 Hz, 1H, H-3), 3.39 (dd, J = 1.6, 3.8 Hz, 1H, H-5), 3.80
(ddd, J = 1.6, 2.0, 7.3 Hz, 1H, H-4), 4.37 (d, J = 11.8 Hz, 1H,
CHOCH2Ph), 4.41 (d, J = 11.8 Hz, 1H, CHOCH2Ph), 4.97 (d,
J = 10.6 Hz, 1H, NOCH2Ph), 5.02 (d, J = 10.6 Hz, 1H, NOCH2Ph),
7.25–7.45 (m, 10H, Ph-H); 13C NMR (100 MHz, CDCl3) d: 16.7,
18.0, 27.9, 35.5, 68.8, 70.3, 70.4, 76.6, 127.5, 127.9, 128.2, 128.4,
128.7, 129.5, 135.1, 137.3, 167.8; MS (ESI): m/z 362 (M+Na+,
100). Anal. Calcd for C21H25NO3: C, 74.31; H, 7.42; N, 4.13; Found:
C, 74.35; H, 7.37; N, 4.52.
4.5.10. (4S,5R)-1,4-Dibenzyloxy-5-phenylpyrrolidin-2-one 18i
Compound 18i: white crystals. Yield over two steps: 64%. Mp
4.5.6. (4S,5R)-1,4-Dibenzyloxy-5-butylpyrrolidin-2-one 18e
Compound 18e: colorless oil. Yield over two steps: 60%.
105–106 °C (Et2O/EtOAc = 8:1); ½a D20
ꢂ
¼ þ53:3 (c 1.1, CHCl3); IR
½
a 2D0
ꢂ
¼ þ84:9 (c 1.0, CHCl3); IR (film)
mmax: 2956, 2930, 2866,
(film) mmax: ;
3025, 2921, 1714, 1449, 1075 cmꢁ1 1H NMR

900
Z.-B. Ye et al. / Tetrahedron: Asymmetry 21 (2010) 895–902
(400 MHz, CDCl3) d: 2.50 (dd, J = 3.1, 17.4 Hz, 1H, H-3), 2.79 (dd,
J = 7.1, 17.4 Hz, 1H, H-3), 3.96 (ddd, J = 2.7, 3.1, 7.1 Hz, 1H, H-4),
4.41 (d, J = 11.6 Hz, 1H, CHOCH2Ph), 4.47 (d, J = 11.6 Hz, 1H,
CHOCH2Ph), 4.49 (d, J = 2.7 Hz, 1H, H-5), 4.84 (d, J = 10.7 Hz, 1H,
NOCH2Ph), 5.05 (d, J = 10.7 Hz, 1H, NOCH2Ph), 7.17–7.41 (m, 15H,
Ph-H); 13C NMR (100 MHz, CDCl3) d: 34.7, 68.6, 71.2, 76.9, 77.3,
126.7, 127.5, 127.9, 128.3, 128.4 (2C), 128.7, 128.9, 129.5, 134.9,
137.1, 137.1, 168.7; MS (ESI): m/z 396 (M+Na+, 100). Anal. Calcd
for C24H23NO3: C, 77.19; H, 6.21; N, 3.75. Found: C, 77.45; H,
5.84; N, 3.78.
4), 4.49 (d, J = 11.8 Hz, 1H, CH2Ph), 4.55 (d, J = 11.8 Hz, 1H, CH2Ph),
6.86 (br s, 1H, NH), 7.27–7.37 (m, 5H, Ph-H) ppm; 13C NMR
(100 MHz, CDCl3) d: 13.9, 19.1, 36.9, 37.0, 60.5, 71.1, 79.1, 127.6,
127.9, 128.5, 137.5, 175.5 ppm; MS (ESI): m/z 256 (M+Na+, 100).
HRESIMS calcd for [C14H19NO2+Na]+: 256.1313. Found: 256.1301.
4.6.5. (4S,5R)-4-Benzyloxy-5-isopropylpyrrolidin-2-one 11d
Colorless oil. Yield: 94%. ½a D20
ꢂ
¼ þ42:6 (c 2.0, CHCl3); IR (film)
m
max: 3216, 2963, 2934, 2876, 1698 cmꢁ1 1H NMR (400 MHz,
;
CDCl3) d: 0.92 (d, J = 5.4 Hz, 3H, CH3), 0.93 (d, J = 5.4 Hz, 3H, CH3),
1.63–1.75 (m, 1H, CHCH3), 2.41 (dd, J = 3.4, 17.5 Hz, 1H, H-3),
2.61 (dd, J = 6.9, 17.5 Hz, 1H, H-3), 3.42–3.44 (m, 1H, H-5), 3.96
(ddd, J = 3.4, 3.4, 6.9 Hz, 1H, H-4), 4.48 (d, J = 11.8 Hz, 1H, CH2Ph),
4.54 (d, J = 11.8 Hz, 1H, CH2Ph), 7.13 (br s, 1H, NH), 7.27–7.37 (m,
5H, Ph-H) ppm; 13C NMR (100 MHz, CDCl3) d: 18.1, 18.6, 31.7,
37.4, 66.7, 70.8, 76.8, 127.7, 127.8, 128.4, 137.5, 175.9 ppm; MS
(ESI): m/z 256 (M+Na+, 100). HRESIMS calcd for [C14H19NO2+Na]+:
256.1313. Found: 256.1302.
4.6. Typical procedure for the SmI2-mediate N–O bond cleavage
of nitrone 18
Preparation of 0.1 M SmI2 solution in THF:31 To 501 mg
(3.34 mol) of samarium powder were added successively 20 mL
of anhydrous THF and I2 (746 mg, 2.94 mmol) at room temperature
under a nitrogen atmosphere. The mixture was stirred for 3 h at
60 °C, during which time the color of the solution changed from
yellow to blue–green.
To a solution of N-benzyloxylactam 18a (110 mg, 0.35 mmol) in
anhydrous THF (7.1 mL) were added successively CH3OH (0.14 mL,
3.5 mmol) and a solution of SmI2 (0.1 M, 14.0 mL, 1.40 mmol) in
THF under a nitrogen atmosphere. After stirring at room tempera-
ture for 3 h, the reaction was quenched with a saturated aqueous
solution of NH4Cl (3 mL) and the mixture was extracted with
EtOAc (3 ꢀ 20 mL). The combined extracts were washed with an
aqueous solution of Na2S2O3, dried over anhydrous Na2SO4, fil-
tered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (EtOAc/
PE = 2:1) to give lactam 11a (72 mg, yield: 100%) as white crystals.
4.6.6. (4S,5R)-4-Benzyloxy-5-butylpyrrolidin-2-one 11e
Colorless oil. Yield: 93%. ½a D20
ꢂ
¼ þ44:8 (c 1.2, CHCl3); IR (film)
m
max: 3216, 2959, 2930, 2859, 1702 cmꢁ1 1H NMR (400 MHz,
;
CDCl3) d: 0.90 (t, J = 6.9 Hz, 3H, CH3), 1.28–1.37 (m, 4H, C2H4CH3),
1.38–1.56 (m, 2H, CH2CHN), 2.40 (dd, J = 3.6, 17.4 Hz, 1H, H-3),
2.62 (dd, J = 6.9, 17.4 Hz, 1H, H-3), 3.58–3.62 (m, 1H, H-5), 3.87
(ddd, J = 3.4, 3.6, 6.9 Hz, 1H, H-4), 4.48 (d, J = 11.8 Hz, 1H, CH2Ph),
4.54 (d, J = 11.8 Hz, 1H, CH2Ph), 7.13 (br s, 1H, NH), 7.26–7.37 (m,
5H, Ph-H) ppm; 13C NMR (100 MHz, CDCl3) d: 13.8, 22.4, 27.8,
34.3, 37.0, 60.7, 71.0, 78.9, 127.6, 127.8, 128.4, 137.5, 175.6 ppm;
MS (ESI): m/z 270 (M+Na+, 100). HRESIMS calcd for [C15H21NO2+-
Na]+: 270.1470. Found: 270.1463.
4.6.1. (4S,5R)-4-Benzyloxy-5-methylpyrrolidin-2-one 11a
Mp 55–57 °C (EtOAc/PE = 1:3) (lit.32 mp 55–57 °C);
4.6.7. (4S,5R)-4-Benzyloxy-5-isobutylpyrrolidin-2-one 11f
Colorless oil. Yield: 100%. ½a D20
ꢂ
¼ þ47:8 (c 0.9, CHCl3); IR (film)
½
a 2D0
ꢂ
¼ þ58:2 (c 1.1, CHCl3) {lit.32
½
a 2D0
ꢂ
¼ þ60:5 (c 1.0, CHCl3)}; IR
m ;
max: 3212, 2955, 2930, 2864, 1694 cmꢁ1 1H NMR (400 MHz,
(film)
m
max: 3241, 1694, 1449, 1379, 1088, 1068 cmꢁ1
;
1H NMR
CDCl3) d: 0.92 (d, J = 6.6 Hz, 3H, CH3), 0.95 (d, J = 6.6 Hz, 3H, CH3),
1.32–1.36 (m, 1H, CHCH3), 1.37–1.42 (m, 1H, CH2CHN), 1.59–1.69
(m, 1H, CH2CHN), 2.40 (dd, J = 3.7, 17.3 Hz, 1H, H-3), 2.62 (dd,
J = 6.8, 17.3 Hz, 1H, H-3), 3.68 (m, 1H, H-5), 3.86 (ddd, J = 3.4, 3.7,
6.8 Hz, 1H, H-4), 4.48 (d, J = 11.8 Hz, 1H, CH2Ph), 4.56 (d,
J = 11.8 Hz, 1H, CH2Ph), 6.39 (br s, 1H, NH), 7.28–7.38 (m, 5H, Ph-
H) ppm; 13C NMR (100 MHz, CDCl3) d: 21.9, 23.1, 25.1, 36.8, 44.0,
58.8, 71.2, 79.6, 127.7, 127.9, 128.5, 137.5, 175.2 ppm; MS (ESI):
m/z 270 (M+Na+, 100). HRESIMS calcd for [C15H21NO2+Na]+:
270.1470. Found: 270.1461.
(400 MHz, CDCl3) d: 1.22 (d, J = 6.5 Hz, 3H, CH3), 2.40 (dd, J = 4.5,
17.2 Hz, 1H, H-3), 2.65 (dd, J = 7.0, 17.2 Hz, 1H, H-3), 3.73 (dq,
J = 3.5, 6.5 Hz, 1H, H-5), 3.83 (ddd, J = 3.5, 4.5, 7.0 Hz, 1H, H-4),
4.55 (d, J = 11.8 Hz, 1H, CH2Ph), 4.49 (d, J = 11.8 Hz, 1H, CH2Ph),
6.54 (br s, 1H, NH), 7.27–7.37 (m, 5H, Ph-H); 13C NMR (100 MHz,
CDCl3) d: 20.4, 37.5, 56.5, 71.4, 80.4, 127.8, 127.9, 128.5, 137.3,
176.5; MS (ESI): m/z 228 (M+Na+, 100).
4.6.2. (4R,5S)-4-Benzyloxy-5-methylpyrrolidin-2-one ent-11a
Mp 57–59 °C; ½a 2D0
¼ ꢁ59:4 (c 1.2, CHCl3).
ꢂ
4.6.8. (4S,5R)-4-Benzyloxy-5-heptylpyrrolidin-2-one 11g
4.6.3. (4S,5R)-4-Benzyloxy-5-ethylpyrrolidin-2-one 11b
Colorless oil. Yield: 91%. ½a D20
ꢂ
¼ þ39:3 (c 1.3, CHCl3); IR (film)
Colorless oil. Yield: 91%. ½a D20
ꢂ
¼ þ44:9 (c 1.5, CHCl3); IR (film)
m ;
max: 3216, 2926, 2851, 1702 cmꢁ1 1H NMR (400 MHz, CDCl3) d:
m
max: 3224, 2963, 2930, 2876, 1694 cmꢁ1
;
1H NMR (400 MHz,
0.88 (t, J = 6.9 Hz, 3H, CH3), 1.21–1.36 (m, 10H, C5H10CH3), 1.39–
1.55 (m, 2H, CH2CHN), 2.40 (dd, J = 3.6, 17.4 Hz, 1H, H-3), 2.62
(dd, J = 6.9, 17.4 Hz, 1H, H-3), 3.58–3.62 (m, 1H, H-5), 3.88 (ddd,
J = 3.4, 3.6, 6.9 Hz, 1H, H-4), 4.48 (d, J = 11.8 Hz, 1H, CH2Ph), 4.55
(d, J = 11.8 Hz, 1H, CH2Ph), 6.50 (br s, 1H, NH), 7.27–7.37 (m, 5H,
Ph-H) ppm; 13C NMR (100 MHz, CDCl3) d: 14.0, 22.6, 25.7, 29.0,
29.3, 31.7, 34.7, 36.9, 60.7, 71.1, 79.0, 127.7, 127.9, 128.5, 137.5,
175.3 ppm; MS (ESI): m/z 312 (M+Na+, 100). HRESIMS calcd for
[C18H27NO2+Na]+: 312.1939. Found: 312.1930.
CDCl3) d: 0.95 (t, J = 7.4 Hz, 3H, CH3), 1.43–1.51 (m, 1H, CHCH3),
1.52–1.61 (m, 1H, CH2CHN), 2.41 (dd, J = 3.6, 17.4 Hz, 1H, H-3),
2.62 (dd, J = 6.9, 17.4 Hz, 1H, H-3), 3.54–3.58 (m, 1H, H-5), 3.83
(ddd, J = 3.4, 3.6, 6.9 Hz, 1H, H-4), 4.49 (d, J = 11.8 Hz, 1H, CH2Ph),
4.54 (d, J = 11.8 Hz, 1H, CH2Ph), 7.13 (br s, 1H, NH), 7.27–7.37 (m,
5H, Ph-H) ppm; 13C NMR (100 MHz, CDCl3) d: 10.0, 27.5, 37.1,
62.1, 71.0, 78.6, 127.6, 127.8, 128.4, 137.5, 175.6 ppm; MS (ESI):
m/z 242 (M+Na+, 100). HRESIMS calcd for [C13H17NO2+Na]+:
242.1157. Found: 242.1146.
4.6.9. (4S,5R)-4-Benzyloxy-5-octylpyrrolidin-2-one 11h
4.6.4. (4S,5R)-4-Benzyloxy-5-propylpyrrolidin-2-one 11c
Colorless oil. Yield: 100%. ½a D20
ꢂ
¼ þ38:3 (c 1.3, CHCl3); IR (film)
Colorless oil. Yield: 96%. ½a D20
ꢂ
¼ þ45:5 (c 2.1, CHCl3); IR (film)
m ;
max: 3212, 2955, 2930, 2851, 1702 cmꢁ1 1H NMR (400 MHz,
m
max: 3220, 2955, 2930, 2872, 1702 cmꢁ1
;
1H NMR (400 MHz,
CDCl3) d: 0.88 (t, J = 6.8 Hz, 3H, CH3), 1.26–1.34 (m, 12H,
C6H12CH3), 1.38–1.54 (m, 2H, CH2CHN), 2.40 (dd, J = 3.6, 17.4 Hz,
1H, H-3), 2.62 (dd, J = 6.9, 17.4 Hz, 1H, H-3), 3.58–3.62 (m, 1H, H-
5), 3.83 (ddd, J = 3.4, 3.6, 6.9 Hz, 1H, H-4), 4.48 (d, J = 11.8 Hz, 1H,
CDCl3) d: 0.94 (t, J = 7.1 Hz, 3H, CH3), 1.31–1.55 (m, 4H, C2H4CH3),
2.41 (dd, J = 3.6, 17.4 Hz, 1H, H-3), 2.63(dd, J = 6.9, 17.4 Hz, 1H,
H-3), 3.60–3.64 (m, 1H, H-5), 3.83 (ddd, J = 3.4, 3.6, 6.9 Hz, 1H, H-

Z.-B. Ye et al. / Tetrahedron: Asymmetry 21 (2010) 895–902
901
CH2Ph), 4.55 (d, J = 11.8 Hz, 1H, CH2Ph), 6.74 (br s, 1H, NH), 7.28–
7.37 (m, 5H, Ph-H) ppm; 13C NMR (100 MHz, CDCl3) d: 14.0, 22.6,
25.7, 29.1, 29.3, 29.4, 31.8, 34.7, 37.0, 60.7, 71.1, 79.0, 127.7,
127.9, 128.4, 137.5, 175.4 ppm; MS (ESI): m/z 326 (M+Na+, 100).
HRESIMS calcd for [C19H29NO2+H]+: 304.2277. Found: 304.2262.
2.5 Hz, m+M, 1H, H-2), 7.26–7.39 (m, m+M, 5H, Ar-H); 13C NMR
(100 MHz, CDCl3) d: 17.1, 17.5, 22.8, 23.8, 28.2, 28.3, 29.6, 30.5,
38.6, 38.7, 46.6, 46.9, 58.8, 58.9, 60.2 (2C), 70.5 (2C), 76.2, 76.6,
79.3, 79.4, 127.5, 127.6, 127.9, 128.0, 128.4, 128.5, 137.0, 137.1,
153.7, 154.2, 172.9, 173.0, 173.6, 173.7; MS (ESI): m/z 425
(M+Na+, 100). HRESIMS calcd for [C22H30N2O5+H]+: 403.2232.
Found: 403.2236.
4.6.10. (4S,5R)-4-Benzyloxy-5-phenylpyrrolidin-2-one 11i
Colorless oil. Yield: 95%.white crystals. Mp 109.7–110.4 °C
(EtOAc/PE = 1:2); ½a D20
ꢂ
¼ þ46:4 (c 2.2, CHCl3); IR (film) mmax
:
4.9. (4R,5S,10S)-1-(N-Butyloxycarbonylprolyl)-4-hydroxyl-5-
methylpyrrolidin-2-one 24
3220, 1702 cmꢁ1 1H NMR (400 MHz, CDCl3) d: 2.45 (dd, J = 4.4,
;
17.2 Hz, 1H, H-3), 2.69 (dd, J = 7.0, 17.2 Hz, 1H, H-3), 4.51 (d,
J = 12.0 Hz, 1H, CH2Ph), 4.54 (d, J = 12.0 Hz, 1H, CH2Ph), 4.72 (d,
J = 3.4 Hz, 1H, H-5), 6.72 (br s, 1H, NH), 7.25–7.38 (m, 10H, Ph-H)
ppm; 13C NMR (100 MHz, CDCl3) d: 36.8, 64.4, 71.5, 82.0, 125.8,
127.6, 127.9, 128.1, 128.4, 128.9, 137.3, 140.0, 175.6 ppm; MS
(ESI): m/z 290 (M+Na+, 100). HRESIMS calcd for [C17H17NO2+Na]+:
290.1157. Found: 290.1154.
To 10% Pd/C (710 mg) was added a solution of compound 23
(790 mg, 1.96 mmol) in anhydrous EtOH (32 mL) and formic acid
(4 mL). The mixture was stirred for 5 h at room temperature. The
reaction mixture was filtered and concentrated under reduced
pressure. The oily residue was purified by flash column chromatog-
raphy on silica gel (EtOAc/PE = 2:1) to give compound 24 (489 mg,
yield: 81%) as
¼ ꢁ40:0 (c 1.3, CHCl3); IR (film)
1696, 1675, 1400, 1240 cmꢁ1 1H NMR (400 MHz, CDCl3) mixture
a
white solid. Mp 140–141 °C (EtOAc/PE);
4.7. 1-tert-Butyl 2-perfluorophenyl (S)-pyrrolidine-1,2-
dicarboxylate 22
½
a 2D0
ꢂ
m
max: 3424, 2976, 1740,
;
of two rotamers (m/M) in a ratio of 1:1.5, d: 1.26 (d, J = 6.7 Hz,
M+m, 3H, CH3), 1.40 (s, m+M, 9H, t-Bu), 1.78–1.95 (m, m+M, 2H,
H-4), 1.90–1.95 (m, m+M, 1H, H-3a), 2.21–2.40 (m, m+M, 1H, H-
3b), 2.40–2.52 (m, m+M, 1H, H-30a), 2.85–2.96 (m, m+M, 1H, H-
30b), 3.15 (br s, 1H, OH), 3.33–3.60 (m, m+M, 2H, H-5), 4.06–4.13
(m, m+M, 1H, H-40), 4.25–4.35 (m, m+M, 1H, H-50), 5.28 (dd,
J = 8.8, 2.5 Hz, m+M, 1H, H-2); 13C NMR (100 MHz, CDCl3) d: 16.7,
17.1, 22.9, 23.8, 28.3, 28.4, 29.7, 30.6, 41.1, 41.2, 46.7, 47.0, 60.3
(2C), 62.3, 62.4, 69.5, 69.8, 79.6 (2C), 153.9, 154.4, 173.3 (2C),
173.8, 173.9; MS (ESI): m/z 335 (M+Na+, 100). HRESIMS calcd for
[C15H24N2O5+H]+: 313.1763. Found: 313.1761.
Acid 21 (215 mg, 1.0 mmol), pentafluorophenol (202 mg,
1.1 mmol), and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide
hydrochloride salt (EDCꢃHCl) (576 mg, 3.0 mmol) were dissolved
in CH2Cl2 (10 mL) at 0 °C. The mixture was stirred at room temper-
ature for 8 h. The reaction mixture was extracted with CH2Cl2
(10 mL ꢀ 3). The combined extracts were washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatogra-
phy on silica gel (CH2Cl2/PE = 1:2) to give compound 22 (320 mg,
yield: 84%) as a colorless oil. ½a D20
ꢂ
¼ ꢁ58 (c 1.2, CHCl3); IR (film)
m
max: 2976, 1793, 1711, 1520, 1388 cmꢁ1 1H NMR (400 MHz,
;
CDCl3) mixture of two rotamers (m/M) in a ratio of 1:2.6, d: 1.45
(s, m+M, 9H, t-Bu), 1.88–2.12 (m, m+M, 2H, H-4), 2.10–2.26 (m,
m+M, 1H, H-3a), 2.31–2.50 (m, m+M, 1H, H-3b), 3.40–3.65 (m,
m+M, 2H, H-5), 4.60 (dd, J = 8.9, 3.7 Hz, m+M, 1H, H-2); 13C NMR
(100 MHz, CDCl3) d: 23.4, 24.4, 28.0, 28.2, 30.0, 31.2, 46.3, 46.5,
58.6 (2C), 80.3, 80.8, 124.9, 136.6, 138.3, 139.1, 139.7, 139.9,
140.0, 142.3, 153.5, 154.2, 169.0, 169.2; MS (ESI): m/z 404
(M+Na+, 100). Anal. Calcd for C16H16F5NO4: C, 50.40; H, 4.23; N,
3.67. Found: C, 50.44; H, 4.23; N, 3.68.
4.10. (5S,10S)-1-(N-tert-Butyloxycarbonylprolyl)-5-
methylpyrrol-2(5H)-one 25
To a solution of compound 24 (46 mg, 0.15 mmol) and DMAP
(1.5 mg, 0.01 mmol) in anhydrous CH2Cl2 (1.5 mL) was added
(Boc)2O (0.04 mL, 0.16 mmol) at 0 °C. The mixture was allowed
to warm to room temperature and stirred for 10 h. The reaction
was quenched with
a saturated aqueous solution of NH4Cl
(2.0 mL). The resulting mixture was extracted with CH2Cl2
(2 mL ꢀ 3). The combined organic phases were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated under re-
duced pressure. The residue was purified by flash column chroma-
tography on silica gel (EtOAc/PE = 1:2) to give compound 25
4.8. (4R,5S,10S)-4-Benzyloxy-1-(N-butyloxycarbonylprolyl)-5-
methylpyrrolidin-2-one 23
To a solution of (4R,5S)-4-(benzyloxy)-5-methylpyrrolidin-2-
one ent-11a (100 mg, 0.47 mmol) in THF (1.6 mL) was added drop-
wise n-BuLi (1.6 M in hexane) (0.29 mL, 0.47 mmol) at ꢁ78 °C. The
mixture was stirred for 15 min. To the resulting mixture was added
a THF solution (1.0 mL) of ester 22 (200 mg, 0.52 mmol). After stir-
ring for 1.5 h at ꢁ78 °C, the reaction temperature was allowed to
rise to ꢁ5 °C. The reaction was quenched with a saturated aqueous
solution of NH4Cl (2.0 mL). The resulting mixture was extracted
with EtOAc (3 mL ꢀ 3). The combined organic phases were washed
with brine, dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (EtOAc/PE = 1:5) to give com-
(31 mg, yield: 71%) as a colorless oil. ½a D20
¼ ꢁ80 (c 1.0, CHCl3)
ꢂ
{lit. ½a 2D0
ꢂ
¼ ꢁ85 (c 1.1, CHCl3);13a
½
a 2D0
ꢂ
¼ ꢁ92 (c 1, CHCl3) for a
max: 2976, 1730, 1699,
5:1 diastereomeric mixture13b}; IR (film)
m
1688, 1400, 1240 cmꢁ1 1H NMR (400 MHz, CDCl3) mixture of
;
two rotamers (m/M) in a ratio of 1:2, d: 1.40 (s, m+M, 9H, t-Bu),
1.45 (d, J = 6.7 Hz, M+m, 3H, CH3), 1.81–2.00 (m, m+M, 2H, H-4),
1.90–2.00 (m, m+M, 1H, H-3a), 2.30–2.47 (m, m+M, 1H, H-3b),
3.40–3.70 (m, m+M, 2H, H-5), 4.70–4.80 (m, m+M, 1H, H-50), 5.35
(dd, J = 9.5, 3.0 Hz, m+M, 1H, H-2), 6.07 (dd, J = 6.0, 1.5 Hz, M+m,
1H, H-30), 7.24 (dd, J = 6.0, 2.0 Hz, M+m, 1H, H-40); 13C NMR
(100 MHz, CDCl3) d: 17.0, 17.8, 22.8, 23.9, 28.3, 28.4, 29.5, 30.5,
46.8, 47.1, 58.0 (2C), 59.7 (2C), 79.4 (2C), 125.4, 125.5, 153.6,
153.7, 153.8, 154.2, 169.8 (2C), 173.0, 173.2; MS (ESI): m/z 317
(M+Na+, 100).
pound 23 (158 mg, yield: 81%) as a pale yellow oil. ½a D20
¼ ꢁ49 (c
ꢂ
0.9, CHCl3); IR (film) mmax: 2976, 1734, 1696, 1672, 1404, 1365,
1232 cmꢁ1 1H NMR (400 MHz, CDCl3) mixture of two rotamers
;
(m/M) in a ratio of 1:1.4, d: 1.28 (d, J = 6.7 Hz, M+m, 3H, CH3),
1.42 (s, m+M, 9H, t-Bu), 1.80–1.98 (m, m+M, 2H, H-4), 1.90–1.98
(m, m+M, 1H, H-3a), 2.25–2.42 (m, m+M, 1H, H-3b), 2.57–2.70
(m, m+M, 1H, H-30a), 2.85–2.96 (m, m+M, 1H, H-30b), 3.40–3.65
(m, m+M, 2H, H-5), 3.77–3.82 (m, m+M, 1H, H-40), 4.48–4.60 (m,
m+M, 2H, ArCH2), 4.55–4.65 (m, m+M, 1H, H-50), 5.30 (dd, J = 8.8,
Acknowledgments
The authors are grateful to the NSF of China (20832005) and the
National Basic Research Program (973 Program) of China (Grant
No. 2010CB833206) for financial support.

902
Z.-B. Ye et al. / Tetrahedron: Asymmetry 21 (2010) 895–902
Tetrahedron: Asymmetry 2002, 13, 1973–1980; (d) Kim, S.-H.; Park, Y.; Choo, H.;
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